At present, the mental health is one of the most serious challenges all countries have to deal with, since at least every fourth person faces such problems during a lifetime. Prevalence of mental health disorders in the European Region is very high. According to the WHO (2006), about 4 of 870 million people in the European Region suffer from schizophrenia; 4 million—from bipolar affective disorders, and 4 million—from panic disorders.
Mental disorders represent the second (after cardiovascular diseases) major cause of disease burden. Their share takes up to 19.5% of DALYs (disability-adjusted life years). More than 40% of all chronic diseases are mental disorders.
The first drugs used for the medication-assisted treatment of schizophrenia—so called typical antipsychotic agents, such as haloperidol, chlorpromazine, etc.—involve a high rate of CNS side effects (convulsions, tardive dyskinesia, akathisia), cardiovascular side effects (arrhythmia, orthostatic hypotension) and endocrine side-effects (weight gain). Motor and movement disorders resulting from the intake of typical antipsychotic agents are often permanent, so their use in treatment of schizophrenia and bipolar disorder is limited and the need to reduce the number of side effects was the main motivator for the development of antipsychotics of new generation. Clozapine (I) developed in the 1960s was the first among such medications. Thereafter both in clinical trials and in the market other atypical antipsychotics appeared. They were dibenzodiazepine derivatives olanzapine (II) and quetiapine (III), as well as compounds of other structural classes: risperidone (IV), ziprasidone (V), aripiprazole (VI).

However, according to various authors, from 5 to 30% of schizophrenic patients are resistant to treatment with conventional antipsychotics, which have limited therapeutic options. The problem of therapeutically-resistant schizophrenia is one of the most important problems in the modern psychiatry.
Treatment resistance may be defined as little or no symptomatic response to multiple (at least two) antipsychotics of different pharmacological classes in average or maximum permissible doses within 6-8 weeks (Lehman, A. F. et. al., Am J Psychiatry, 2004, 161, 1-56).
Based on analysis of data on clinical predictors of drug resistance, a number of authors have described its various types, which is very important from a practical standpoint. It has been proposed to distinguish between resistance to antipsychotic treatment, which is observed since therapy commencement (anticipated low curability, primary resistance), and resistance emerging in the course of treatment (anticipated insufficient curability, adaptation to psychotropic effects of neuroleptics, secondary resistance). Current reinterpretation of this differentiation suggests that the primary resistance is observed under the initial “malignant” course of endogenous process (pubescent insanity, continuous progressive course). The secondary resistance has syndromological basis to a greater extent. In this case, the “non-response” to therapy is associated with the emergence of complex of deep-rooted symptoms (chronic delusions, various positive disorders in the structure of disorder, diminished symptoms), rather than with the peculiarities of schizophrenia.
The pathological mechanisms of resistance to antipsychotic therapy have not been determined yet. Aside from fewness, contratiety and fragmentation of the data obtained, this can also be explained with the lack of a clear understanding of complicated pathogenesis of schizophrenia. The role of features of abnormalities in different elements of neurotransmitter systems in various brain regions (pharmacodynamic factor), immunological and endocrine factors is being discussed. The significance of features of individual pharmacokinetics, for example, reduction of bioavailability (and, therefore, antipsychotic activity) of neuroleptic due to the individual features of absorption processes, metabolism and excretion, should not be underestimated. A major role in the formation of resistance belongs to genetic factors, which form the basis of pharmacodynamic and pharmacokinetic features of resistant patients. For example, the importance of genes responsible for the formation and functioning of dopamine, serotonin and other receptors; genes of enzymes that destroy neurotransmitters; genes of cytochrome P450 enzymes; genes of drug transporter proteins.
The choice of therapeutic tactics in case of resistance to antipsychotic therapy is extremely difficult. Various drug and non-drug methods of treatment for treatment-resistant forms of schizophrenia have been proposed. These are clozapine therapy, electroconvulsive therapy, proceeding to the therapy with a typical neuroleptic, proceeding to the therapy with an atypical neuroleptic, use of high and ultra-high doses of neuroleptics, temporary withdrawal (cessation) of antipsychotic therapy, combination of several neuroleptics, combination of antipsychotic and forced insulin shock therapy, and other methods.
Special attention should be paid the data on high efficiency of atypical neuroleptic clozapine in the treatment of schizophrenic patients resistant to antipsychotic therapy. Its efficiency has been proved in the very first large-scale trial (Kane, J. et. al., Arch Gen Psychiatry, 1988, 45, 789-96) and then has been repeatedly confirmed thereafter. It has been proven in precisely designed trials, the methodology of which is fully consistent with the principles of evidence-based medicine (Wahlbeck, K. et. al., Cochrane Database Syst Rev, 2000, CD000059). The number of patients with significant improvements due to administration of clozapine is about twice the number for traditional neuroleptics. It is believed that the clozapine therapy weakens positive symptoms of 30-60% of patients resistant to typical neuroleptics. Clozapine is recognized as the only antipsychotic agent, efficiency of which in resistant cases has been proven. There are certain controversies as to the timing of onset of therapeutic effect with clozapine in resistant cases of schizophrenia. According to some estimates, the condition of patients can be improved within a few months (Rosenheck, R. et. al., Schizophr Bull, 1999, 25, 709-19). Results of other trials evidence more extended time frames of onset of therapeutic effect (Spina, E. et. al., Psychopharmacology (Berl), 2000, 148, 83-9). Regardless, clozapine is the only neuroleptic officially recommended for use in case of resistance to other antipsychotic agents. At the same time it should be noted that clozapine is recommended both in case of in primary and secondary forms of resistance.
In case of long-term use, clozapine allows for improvement of condition of 60% of patients suffering from treatment-resistant forms of schizophrenia. Clozapine eliminates both the positive symptoms of schizophrenia (delusion, auditory hallucinations, thought disorders) and negative symptoms (flat affect, poverty of speech) and cognitive impairments.
The main disadvantage of clozapine, due to which the medication was recalled from the market in some countries in 1975, is the risk of agranulocytosis, a life-threatening condition, which entails decrease in the number of leukocytes and neutrophils in the blood. The probability of agranulocytosis occurrence among patients taking clozapine reaches 0.8% (Alvir, J. M. et. al., N Engl J Med, 1993, 329, 162-7), and 3-4% of them die. The use of clozapine for the treatment of some forms of schizophrenia was again permitted upon condition of weekly monitoring of the count of leukocytes and neutrophils in the blood. Because of the risk of agranulocytosis, clozapine is used only in cases when the use of other medications is ineffective. In addition, clozapine is difficult to administer due to frequent cases of autonomic dysfunction (tachycardia, orthostatism, sialorrhea, constipation) and significant sedation.
Despite many years of attempts to develop a safer and more effective agent for the treatment of schizophrenia, none of them had better efficacy than clozapine, the best atypical antipsychotic in its class. At the same time, the risk of tachycardia, orthostatism, sedation and agranulocytosis imposes substantial limitations on the clinical use of clozapine.